Urea- and urethane-substituted acylureas, process for their preparation and their use

ABSTRACT

The invention relates to urea- and urethane-substituted acylureas and to their physiologically tolerated salts and physiologically functional derivatives. In particular, the invention relates to the compounds of the formula I 
                         
wherein the radicals have meanings described herein, and to their physiologically tolerated salts and to processes for their preparation. The compounds are suitable for example as antidiabetics.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. § 119 to DE10231371.7-42 filed Jul. 11, 2002. This application also claims priorityunder 35 U.S.C. § 120 to U.S. Provisional No. 60/425,600, filed Nov. 12,2002. Both of these documents are incorporated herein by reference intheir entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to urea- and urethane-substituted acylureas and totheir physiologically tolerated salts and physiologically functionalderivatives.

2. Description of the Prior Art

EP 0 221 847 describes compounds of similar structure for controllingpests.

SUMMARY OF THE INVENTION

In a preferred embodiment, the invention provides compounds whichprevent and treat type 2 diabetes. The compounds of the inventionproduce a marked reduction in blood glucose levels.

In another preferred embodiment, the invention provides a pharmaceuticalcomposition comprising one or more compounds of the instant inventionand at least one other active ingredient.

In another preferred embodiment, the invention provides a pharmaceuticalcomposition comprising one or more of the compounds of the instantinvention.

In another preferred embodiment, the invention provides a method forreducing blood glucose, comprising administering to a subject in needthereof, one or more compounds of the instant invention.

In another preferred embodiment, the invention provides a method fortreating type 2 diabetes, comprising administering to a subject in needthereof, one or more compounds of the instant invention.

In another preferred embodiment, the invention provides a method fortreating disturbances of lipid and carbohydrate metabolism, comprisingadministering to a subject in need thereof, one or more compounds of theinstant invention.

In another preferred embodiment, the invention provides a method fortreating arteriosclerotic manifestations, comprising administering to asubject in need thereof, one or more compounds of the instant invention.

In another preferred embodiment, the invention provides a method fortreating insulin resistance, comprising administering to a subject inneed thereof, one or more compounds of the instant invention.

In another preferred embodiment, the invention provides a process forproducing a pharmaceutical composition comprising one or more of thecompounds of the invention, which comprises mixing the active ingredientwith a pharmaceutically suitable carrier and converting this mixtureinto a form suitable for administration.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention therefore relates to compounds of the formula I

in which

-   -   W, X, Y are, independently of one another, O or S;    -   R9, R10, R11, R12 are, independently of one another, H, F, Cl,        Br, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, O—(C₂-C₆)-alkenyl,        O—(C₂-C₆)-alkynyl, O—SO₂—(C₁-C₄)-alkyl, O—SO₂-phenyl, where the        phenyl ring may be substituted up to twice by F, Cl, Br, CN,        OR13, R13, CF₃, OCF₃, COOR13 or CON(R14)(R15), S—(C₂-C₆)-alkyl,        S—(C₂-C₆)-alkenyl, S—(C₂-C₆)-alkynyl, SO—(C₁-C₆)-alkyl,        SO₂—(C₁-C₆)-alkyl, SO₂—NH₂, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,        (C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl,        (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl, —COOR13,        (C₁-C₆)-alkylene-COOR13, CON(R14)(R15), —N(R14)(R15),        (C₁-C₆)-alkylene-N(R14)(R15), NH—COR13, NH—CO-phenyl,        NH—SO₂-phenyl or phenyl, where the phenyl ring may be        substituted up to twice by F, Cl, Br, CN, OR13, R13, CF₃, OCF₃,        COOR13 or CON(R14)(R15);    -   R13 is H, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl,        (C₃-C₇)-cycloalkyl or (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl;    -   R1, R2 are, independently of one another, H, (C₁-C₆)-alkyl,        where alkyl may be substituted by OH, O—(C₁-C₄)-alkyl or        N(R14)(R15), or O—(C₁-C₆)-alkyl, O—(C₂-C₆)-alkenyl,        O—(C₂-C₆)-alkynyl, CO—(C₁-C₆)-alkyl, CO—(C₂-C₆)-alkenyl,        CO—(C₂-C₆)-alkynyl, COOR13 or —COOR13, (C₁-C₆)-alkylene-COOR13;    -   R3, R4, R5, R6 are, independently of one another, H, F, Cl, Br,        OH, CF₃, NO₂, CN, OCF₃, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,        (C₂-C₆)-alkynyl, O—(C₁-C₁₀)-alkyl, O—(C₂-C₁₀)-alkenyl,        O—(C₂-C₁₀)-alkynyl, S—(C₁-C₆)-alkyl, S—(C₂-C₆)-alkenyl,        S—(C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl,        (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl, where alkyl, alkenyl, alkynyl        and cycloalkyl may be substituted more than once by F, Cl, Br,        SO-phenyl, SO₂-phenyl, where the phenyl ring may be substituted        by F, Cl, Br or R13, or OR13, COOR13, CON(R14)(R15), N(R14)(R15)        or CO-heteroalkyl, O—SO—(C₁-C₆)-alkyl, O—SO₂—(C₁-C₆)-alkyl,        O—SO₂—(C₆-C₁₀)-aryl, O—(C₆-C₁₀)-aryl, where aryl may be        substituted up to twice by F, Cl, CN, OR13, R13, CF₃ or OCF₃,        SO—(C₁-C₆)-alkyl, SO₂—(C₁-C₆)-alkyl, SO₂—(C₆-C₁₀)-aryl, where        the phenyl ring may be substituted up to twice by F, Cl, Br, CN,        OR13, R13, CF₃, OCF₃, COOR13 or CON(R14)(R15), SO₂—N(R14)(R15),        COOR13, CO-heteroalkyl, N(R14)(R15) or heteroalkyl;    -   R14, R15 are, independently of one another, H, (C₁-C₆)-alkyl,        where alkyl may be substituted by N(R13)₂, (C₂-C₆)-alkenyl,        (C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl,        (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl, CO—(C₁-C₆)-alkyl,        COO—(C₁-C₆)-alkyl, COO—(C₁-C₆)-alkylene-OCO—(C₁-C₆)-alkyl,        CO-phenyl, COO-phenyl, COO—(C₁-C₆)-alkenyl-phenyl, OH,        O—(C₁-C₆)-alkyl, O—(C₁-C₆)-alkenyl-phenyl or NH₂;    -   or the radicals R14 and R15 form with the nitrogen atom to which        they are bonded a 3-7-membered, saturated heterocyclic ring        which may comprise up to 3 heteroatoms selected from N, O or S,        where the heterocyclic ring may be substituted up to three times        by F, Cl, Br, OH, oxo, N(R16)(R17) or (C₁-C₄)-alkyl;    -   R16, R17 are, independently of one another, H, (C₁-C₆)-alkyl,        where alkyl may be substituted by N(R13)₂, (C₂-C₆)-alkenyl,        (C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl,        (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl, CO—(C₁-C₆)-alkyl,        COO—(C₁-C₆)-alkyl, COO—(C₁-C₆)-alkylene-OCO—(C₁-C₆)-alkyl,        CO-phenyl, COO-phenyl, COO—(C₁-C₆)-alkenyl-phenyl, OH,        O—(C₁-C₆)-alkyl, O—(C₁-C₆)-alkenyl-phenyl or NH₂;    -   heteroalkyl is a 3-7-membered, saturated or up to triunsaturated        heterocyclic ring which may comprise up to 4 heteroatoms which        correspond to N, O or S, where the heterocyclic ring may be        substituted up to three times by F, Cl, Br, CN, oxo,        (C₁-C₄)-alkyl, —COOR13, (C₁-C₄)-alkylene-COOR13, CON(R14)(R15),        OR13, N(R14)(R15) or phenyl, where phenyl may be substituted by        COOR13;    -   R7 is H, (C₁-C₆)-alkyl, where alkyl may be substituted by OR13        or N(R14)(R15), O—(C₁-C₆)-alkyl, CO—(C₁-C₆)-alkyl, —COOR13, or        (C₁-C₆)-alkylene-COOR13;    -   R8 is N(R18)(R19) or OR20;    -   or R8 and R4 together form the group —NH—CO—;    -   R18, R19 are, independently of one another, H, (C₁-C₁₀)-alkyl,        (C₂-C₁₀)-alkenyl, (C₂-C₁₀)-alkynyl, (C₃-C₇)-cycloalkyl,        (C₃-C₇)-cycloalkyl-(C₁-C₆)-alkyl, (C₆-C₁₀)-aryl,        (C₆-C₁₀)-aryl-(C₁-C₄)-alkyl, (C₆-C₁₀)-aryl-(C₂-C₄)-alkenyl,        (C₆-C₁₀)-aryl-(C₂-C₄)-alkynyl, heteroaryl,        heteroaryl-(C₁-C₄)-alkyl, heteroaryl-(C₂-C₄)-alkenyl,        heteroaryl-(C₂-C₄)-alkynyl, where alkyl, alkenyl, alkynyl and        cycloalkyl may be substituted one or more times by F, Cl, CN,        OR13, R13, CF₃, OCF₃, (C₆-C₁₀)-aryl, NH—C(═NR14)-N(R14)(R15),        N(R14)(R15), C(═NR14)-N(R14)(R15), COOR13 or CON(R14)(R15), and        where aryl may be substituted more than once by F, Cl, CN,        O—(C₁-C₆)-alkyl, O—(C₂-C₆)-alkenyl, (C₁-C₆)-alkyl,        (C₂-C₆)-alkenyl, CO—(C₁-C₆)-alkyl, CO—(C₂-C₆)-alkenyl, where        alkyl and alkenyl may be substituted more than once by F, Cl,        CH₃, OCH₃ or CN, NH—C(═NR14)-N(R14)(R15), N(R14)(R15),        C(═NR14)-N(R14)(R15), COOR13, CON(R14)(R15), O-phenyl, phenyl or        pyridyl; COOR13, CON—(R14)(R15), CO-heteroalkyl,        CO—(C₆-C₁₀)-aryl or SO₂—(C₆-C₁₀)-aryl, where aryl may be        substituted up to twice by F, Cl, CN, OH, (C₁-C₆)-alkyl,        O—(C₁-C₆)-alkyl, CF₃, OCF₃, COOR13 or CON(R14)(R15);    -   or the radicals R18 and R19 form with the nitrogen atom to which        they are bonded a 3-7-membered, saturated heterocyclic ring        which may comprise up to 3 heteroatoms selected from the group        of N, O or S, where the heterocyclic ring may be substituted up        to three times by F, Cl, Br, OH, oxo, N(R16)(R17) or        (C₁-C₄)-alkyl;    -   R20 is (C₁-C₁₀)-alkyl, (C₂-C₁₀)-alkenyl, (C₂-C₁₀)-alkynyl,        (C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₆)-alkyl,        (C₆-C₁₀)-aryl, (C₆-C₁₀)-aryl-(C₁-C₄)-alkyl,        (C₆-C₁₀)-aryl-(C₂-C₄)-alkenyl or (C₆-C₁₀)-aryl-(C₂-C₄)-alkynyl,        where aryl may be substituted more than once by F, Cl, CN,        O—(C₁-C₆)-alkyl, O—(C₂-C₆)-alkenyl, (C₁-C₆)-alkyl,        (C₂-C₆)-alkenyl, CO—(C₁-C₆)-alkyl, CO—(C₂-C₆)-alkenyl, where        alkyl and alkenyl may be substituted more than once by F, Cl,        CH₃, OCH₃ or CN, NH—C(═NR14)-N(R14)(R15), N(R14)(R15),        C(═NR14)-N(R14)(R15), COOR13, CON(R14)(R15), O-phenyl, phenyl or        pyridyl, where phenyl may be substituted by F, Cl, CN or        (C₁-C₆)-alkyl;

and their physiologically tolerated salts, provided the radicals R6, R7,X, Y and R8 do not have the following meanings at the same time:

-   -   R6 is H, CL, CF₃, CH₃;    -   R7 is H;    -   X is O;    -   Y is O, S;    -   R8 is substituted or unsubstituted NH-phenyl.

In a preferred embodiment, the invention provides compounds of theformula 1a:

wherein

-   -   R9 is F, Cl, Br, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl,        O—(C₂-C₆)-alkenyl, O—(C₂-C₆)-alkynyl, O—SO₂—(C₁-C₄)-alkyl,        O—SO₂-phenyl, where the phenyl ring may be substituted up to        twice by F, Cl, Br, CN, OR13, R13, CF₃, OCF₃, COOR13 or        CON(R14)(R15), or S—(C₁-C₆)-alkyl, S—(C₂-C₆)-alkenyl,        S—(C₂-C₆)-alkynyl, SO—(C₁-C₆)-alkyl, SO₂—(C₁-C₆)-alkyl, SO₂-NH₂,        (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl,        (C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl, —COOR13,        (C₁-C₆)-alkylene-COOR13, CON(R14)(R15), —N(R14)(R15),        (C₁-C₆)-alkylene-N(R14)(R15), NH—COR13, NH—CO-phenyl,        NH-SO₂-phenyl or phenyl, where the phenyl ring may be        substituted up to twice by F, Cl, Br, CN, OR13, R13, CF₃, OCF₃,        COOR13 or CON(R14)(R15);    -   R10, R11, R12 independently of one another are H, F, Cl, Br, OH,        CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, O—(C₂-C₆)-alkenyl,        O—(C₂-C₆)-alkynyl, O—SO₂—(C₁-C₄)-alkyl, O—SO₂-phenyl, where the        phenyl ring may be substituted up to twice by F, Cl, Br, CN,        OR13, R13, CF₃, OCF₃, COOR13 or CON(R14)(R15), S—(C₁-C₆)-alkyl,        S—(C₂-C₆)-alkenyl, S—(C₂-C₆)-alkynyl, SO—(C₁-C₆)-alkyl,        SO₂—(C₁-C₆)-alkyl, SO₂—NH₂, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,        (C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl,        (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl, —COOR13,        (C₁-C₆)-alkylene-COOR13, COOR 13, CON(R14)(R15), —N(R14)(R15),        (C₁-C₆)-alkylene-N(R14)(R15), C₁-C₆)-alkylene-N (R14)(R15),        N(R14)(R15), NH—COR13, NH—CO-phenyl, NH—SO₂-phenyl or phenyl,        where the phenyl ring may be substituted up to twice by F, Cl,        Br, CN, OR13, R13, CF₃, OCF₃, COOR13 or CON(R14)(R15);    -   R13 is H, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl,        (C₃-C₇)-cycloalkyl or (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl;    -   R3, R4, R5 are independently of one another H, F, Cl, Br, OH,        CF₃, NO₂, CN, OCF₃, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,        (C₂-C₆)-alkynyl, O—(C₁-C₁₀)-alkyl, O—(C₂-C₁₀)-alkenyl,        O—(C₂-C₁₀)-alkynyl, S—(C₁-C₆)-alkyl, S—(C₂-C₆)-alkenyl,        S—(C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl,        (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl, where alkyl, alkenyl, alkynyl        and cycloalkyl may be substituted more than once by F, Cl, Br,        SO-phenyl, SO₂-phenyl, where the phenyl ring may be substituted        by F, Cl, Br or R13, or OR13, COOR13, CON(R14)(R15), N(R14)(R15)        or CO-heteroalkyl, O—SO—(C₁-C₆)-alkyl, O—SO₂—(C₁-C₆)-alkyl,        O—SO₂—(C₆-C₁₀)-aryl, O—(C₆-C₁₀)-aryl, where aryl may be        substituted up to twice by F, Cl, CN, OR13, R13, CF₃ or OCF₃,        SO—(C₁-C₆)-alkyl, SO₂—(C₁-C₆)-alkyl, SO₂—(C₆-C₁₀)-aryl, where        the phenyl ring may be substituted up to twice by F, Cl, Br, CN,        OR13, R13, CF₃, OCF₃, COOR13 or CON(R14)(R15), SO₂—N(R14)(R15),        COOR13, CO-heteroalkyl, N(R14)(R15) or heteroalkyl;    -   R6 is F, Cl, Br, OH, CF₃, NO₂, CN, OCF₃, (C₁-C₆)-alkyl,        (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, O—(C₁-C₁₀)-alkyl,        O—(C₂-C₁₀)-alkenyl, O—(C₂-C₁₀)-alkynyl, S—(C₁-C₆)-alkyl,        S—(C₂-C₆)-alkenyl, S—(C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl,        (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl, where alkyl, alkenyl, alkynyl        and cycloalkyl may be substituted more than once by F, Cl, Br,        SO-phenyl, SO₂-phenyl, where the phenyl ring may be substituted        by F, Cl, Br or R13, or OR13, COOR13, CON(R14)(R15), N(R14)(R15)        or CO-heteroalkyl, or O—SO—(C₁-C₆)-alkyl, O—SO₂—(C₁-C₆)-alkyl,        O—SO₂—(C₆-C₁₀)-aryl, O—(C₆-C₁₀)-aryl, where aryl may be        substituted up to twice by F, Cl, CN, OR13, R13, CF₃ or OCF₃, or        SO—(C₁-C₆)-alkyl, SO₂—(C₁-C₆)-alkyl, SO₂—(C₆-C₁₀)-aryl, where        the phenyl ring may be substituted up to twice by F, Cl, Br, CN,        OR13, R13, CF₃, OCF₃, COOR13 or CON(R14)(R15), or        SO₂—N(R14)(R15), COOR13, CO-heteroalkyl, N(R14)(R15) or        heteroalkyl;    -   R14, R15 independently of one another are H, (C₁-C₆)-alkyl,        where alkyl may be substituted by N(R13)₂, (C₂-C₆)-alkenyl,        (C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl,        (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl, CO—(C₁-C₆)-alkyl,        COO—(C₁-C₆)-alkyl, COO—(C₁-C₆)-alkylene-OCO—(C₁-C₆)-alkyl,        CO-phenyl, COO-phenyl, COO—(C₁-C₆)-alkenyl-phenyl, OH,        O—(C₁-C₆)-alkyl, O—(C₁-C₆)-alkenyl-phenyl or NH₂;    -   or the radicals R14 and R15 form with the nitrogen atom to which        they are bonded a 3-7-membered, saturated heterocyclic ring        which may comprise up to 3 heteroatoms selected from the group        of N, O or S, where the heterocyclic ring may be substituted up        to three times by F, Cl, Br, OH, oxo, N(R16)(R17) or        (C₁-C₄)-alkyl;    -   R16, R17 independently of one another are H, (C₁-C₆)-alkyl,        where alkyl may be substituted by N(R13)₂, (C₂-C₆)-alkenyl,        (C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl,        (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl, CO—(C₁-C₆)-alkyl,        COO—(C₁-C₆)-alkyl, COO—(C₁-C₆)-alkylene-OCO—(C₁-C₆)-alkyl,        CO-phenyl, COO-phenyl, COO—(C₁-C₆)-alkenyl-phenyl, OH,        O—(C₁-C₆)-alkyl, O—(C₁-C₆)-alkenyl-phenyl or NH₂;    -   heteroalkyl is a 3-7-membered, saturated or up to triunsaturated        heterocyclic ring which may comprise up to 4 heteroatoms        selected from N, O or S, where the heterocyclic ring may be        substituted up to three times by F, Cl, Br, CN, oxo,        (C₁-C₄)-alkyl, —COOR13, (C₁-C₄)-alkylene-COOR13, COOR13,        CON(R14)(R15), OR13 or N(R14)(R15) or phenyl, where phenyl may        be substituted by COOR13;    -   R8 is N(R18)(R19) or OR20;    -   or R8 and R4 together form the group —NH—CO—;    -   R18, R19 independently of one another are H, (C₁-C₁₀)-alkyl,        (C₂-C₁₀)-alkenyl, (C₂-C₁₀)-alkynyl, (C₃-C₇)-cycloalkyl,        (C₃-C₇)-cycloalkyl-(C₁-C₆)-alkyl, (C₆-C₁₀)-aryl,        (C₆-C₁₀)-aryl-(C₁-C₄)-alkyl, (C₆-C₁₀)-aryl-(C₂-C₄)-alkenyl,        (C₆-C₁₀)-aryl-(C₂-C₄)-alkynyl, heteroaryl,        heteroaryl-(C₁-C₄)-alkyl, heteroaryl-(C₂-C₄)-alkenyl,        heteroaryl-(C₂-C₄)-alkynyl, where alkyl, alkenyl, alkynyl and        cycloalkyl may be substituted more than once by F, Cl, CN, OR13,        R13, CF₃, OCF₃, (C₆-C₁₀)-aryl, NH—C(═NR14)-N(R14)(R15),        N(R14)(R15), C(═NR14)-N(R14)(R15), COOR13 or CON(R14)(R15), and        where aryl may be substituted more than once by F, Cl, CN,        O—(C₁-C₆)-alkyl, O—(C₂-C₆)-alkenyl, (C₁-C₆)-alkyl,        (C₂-C₆)-alkenyl, CO—(C₁-C₆)-alkyl, CO—(C₂-C₆)-alkenyl, where        alkyl and alkenyl may be substituted more than once by F, Cl,        CH₃, OCH₃ or CN, or NH—C(═NR14)-N(R14)(R15), N(R14)(R15),        C(═NR14)-N(R14)(R15), COOR13, CON(R14)(R15), O—phenyl, phenyl or        pyridyl; COOR13, CON—(R14)(R15), CO-heteroalkyl,        CO—(C₆-C₁₀)-aryl or SO₂—(C₆-C₁₀)-aryl, where aryl may be        substituted up to twice by F, Cl, CN, OH, (C₁-C₆)-alkyl,        O—(C₁-C₆)-alkyl, CF₃, OCF₃, COOR13 or CON(R14)(R15);    -   or the radicals R18 and R19 form together with the nitrogen atom        to which they are bonded a 3-7-membered, saturated heterocyclic        ring which may comprise up to 3 heteroatoms selected from the        group of N, O or S, where the heterocyclic ring may be        substituted up to three times by F, Cl, Br, OH, oxo, N(R16)(R17)        or (C₁-C₄)-alkyl;    -   R20 is (C₁-C₁₀)-alkyl, (C₂-C₁₀)-alkenyl, (C₂-C₁₀)-alkynyl,        (C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₆)-alkyl,        (C₆-C₁₀)-aryl, (C₆-C₁₀)-aryl-(C₁-C₄)-alkyl,        (C₆-C₁₀)-aryl-(C₂-C₄)-alkenyl or (C₆-C₁₀)-aryl-(C₂-C₄)-alkynyl,        where aryl may be substituted more than once by F, Cl, CN,        O—(C₁-C₆)-alkyl, O—(C₂-C₆)-alkenyl, (C₁-C₆)-alkyl,        (C₂-C₆)-alkenyl, CO—(C₁-C₆)-alkyl, CO—(C₂-C₆)-alkenyl, where        alkyl and alkenyl may be substituted more than once by F, Cl,        CH₃, OCH₃ or CN, or NH—C(═NR14)-N(R14)(R15), N(R14)(R15),        C(═NR14)-N(R14)(R15), COOR13, CON(R14)(R15), O-phenyl, phenyl or        pyridyl, where phenyl may be substituted by F, Cl, CN or        (C₁-C₆)-alkyl;    -   and their physiologically tolerated salts,    -   provided the radical R8 is not phenyl.

Preferably, compounds of formula 1a have the following meanings:

-   -   R9, R10, R11 independently of one another are F or Cl;    -   R12 is H;    -   R13 is H, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl,        (C₃-C₇)-cycloalkyl or (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl;    -   R6 is F, Cl, CF₃, OCF₃, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,        (C₂-C₆)-alkynyl, O—(C₁-C₁₀)-alkyl, O—(C₂-C₁₀)-alkenyl,        O—(C₂-C₁₀)-alkynyl, (C₃-C₇)-cycloalkyl,        (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl, N(R14)(R15) or Cl;        heteroalkyl, where alkyl, alkenyl, alkynyl and cycloalkyl may be        substituted more than once by F, COOR13, CON(R14)(R15) or        N(R₁₄)(R₁₅);    -   R14, R15 are independently of one another H, (C₁-C₆)-alkyl,        where alkyl may be substituted by N(R13)₂;    -   Heteroalkyl is a 3-7-membered, saturated or up to triunsaturated        heterocyclic ring which may comprise up to 4 heteroatoms which        correspond to N, O or S, where the heterocyclic ring may be        substituted up to three times by F, Cl, Br, CN, oxo,        (C₁-C₄)-alkyl, —COOR13, (C₁-C₄)-alkylene-COOR13, CON(R14)(R15),        OR13 or N(R14)(R15) or phenyl, where phenyl may be substituted        by COOR13;    -   R8 is N(R18)(R19) or OR20;    -   or R8 and R4 together form the group —NH—CO—;    -   R18, R19 are independently of one another H, (C₁-C₁₀)-alkyl,        (C₂-C₁₀)-alkenyl, (C₂-C₁₀)-alkynyl, (C₃-C₇)-cycloalkyl,        (C₃-C₇)-cycloalkyl-(C₁-C₆)-alkyl, (C₆-C₁₀)-aryl,        (C₆-C₁₀)-aryl-(C₁-C₄)-alkyl, (C₆-C₁₀)-aryl-(C₂-C₄)-alkenyl,        (C₆-C₁₀)-aryl-(C₂-C₄)-alkynyl, heteroaryl,        heteroaryl-(C₁-C₄)-alkyl, heteroaryl-(C₂-C₄)-alkenyl,        heteroaryl-(C₂-C₄)-alkynyl, where alkyl, alkenyl, alkynyl and        cycloalkyl may be substituted more than once by F, Cl, CN, OR13,        R13, CF₃, OCF₃, (C₆-C₁₀)-aryl, NH—C(═NR14)-N(R14)(R15),        N(R14)(R15), C(═NR14)-N(R14)(R15), COOR13 or CON(R14)(R15), and        where aryl may be substituted more than once by F, Cl, CN,        O—(C₁-C₆)-alkyl, O—(C₂-C₆)-alkenyl, (C₁-C₆)-alkyl,        (C₂-C₆)-alkenyl, CO—(C₁-C₆)-alkyl, CO—(C₂-C₆)-alkenyl, where        alkyl and alkenyl may be substituted more than once by F, Cl,        CH₃, OCH₃ or CN, or NH—C(═NR14)-N(R14)(R15), N(R14)(R15),        C(═NR14)-N(R14)(R15), COOR13, CON(R14)(R15), O-phenyl, phenyl or        pyridyl; COOR13, CON—(R14)(R15), CO-heteroalkyl,        CO—(C₆-C₁₀)-aryl or SO₂—(C₆-C₁₀)-aryl, where aryl may be        substituted up to twice by F, Cl, CN, OH, (C₁-C₆)-alkyl,        O—(C₁-C₆)-alkyl, CF₃, OCF₃, COOR13 or CON(R14)(R15);    -   or the radicals R18 and R19 form together with the nitrogen atom        to which they are bonded a 3-7-membered, saturated heterocyclic        ring which may comprise up to 2 further heteroatoms from the        group of N, O or S, where the heterocyclic ring may be        substituted up to three times by F, Cl, Br, OH, oxo, N(R16)(R17)        or (C₁-C₄)-alkyl;    -   R20 is (C₁-C₁₀)-alkyl, (C₂-C₁₀)-alkenyl, (C₂-C₁₀)-alkynyl,        (C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₆)-alkyl,        (C₆-C₁₀)-aryl, (C₆-C₁₀)-aryl-(C₁-C₄)-alkyl,        (C₆-C₁₀)-aryl-(C₂-C₄)-alkenyl or (C₆-C₁₀)-aryl-(C₂-C₄)-alkynyl,        where aryl may be substituted more than once by F, Cl, CN, or        O—(C₁-C₆)-alkyl.

The alkyl radicals in the substituents R1, R2, R3, R4, R5, R6, R7, R8,R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19 or R20 may be bothstraight-chain and branched.

If radicals or substituents may occur more than once in the compounds ofthe formula I, such as, for example, COOR13, they may all, independentlyof one another, have the stated meanings and be identical or different.

The invention relates to compounds of the formula I in the form of theirracemates, racemic mixtures and pure enantiomers, and to theirdiastereomers and mixtures thereof.

Pharmaceutically acceptable salts are, because their solubility in wateris greater than that of the initial or basic compounds, particularlysuitable for medical applications. These salts must have apharmaceutically acceptable anion or cation. Suitable pharmaceuticallyacceptable acid addition salts of the compounds of the invention aresalts of inorganic acids such as hydrochloric acid, hydrobromic,phosphoric, metaphosphoric, nitric and sulfuric acid, and of organicacids such as, for example, acetic acid, benzenesulfonic, benzoic,citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic,lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonicand tartaric acid. Suitable pharmaceutically acceptable basic salts areammonium salts, alkali metal salts (such as sodium and potassium salts),alkaline earth metal salts (such as magnesium and calcium salts), andsalts of trometamol (2-amino-2-hydroxymethyl-1,3-propanediol),diethanolamine, lysine or ethylenediamine.

Salts with a pharmaceutically unacceptable anion such as, for example,trifluoroacetate likewise belong within the framework of the inventionas useful intermediates for the preparation or purification ofpharmaceutically acceptable salts and/or for use in nontherapeutic, forexample in vitro, applications.

The term “physiologically functional derivative” used herein refers toany physiologically tolerated derivative of a compound of the formula Iof the invention, for example an ester, which on administration to amammal such as, for example, a human is able to form (directly orindirectly) a compound of the formula I or an active metabolite thereof.

Physiologically functional derivatives include prodrugs of the compoundsof the invention, as described, for example, in H. Okada et al., Chem.Pharm. Bull. 1994, 42, 57-61. Such prodrugs can be metabolized in vivoto a compound of the invention. These prodrugs may themselves be activeor not.

The compounds of the invention may also exist in various polymorphousforms, for example as amorphous and crystalline polymorphous forms. Allpolymorphous forms of the compounds of the invention belong within theframework of the invention and are a further aspect of the invention.

All references to “compound(s) of formula I” hereinafter refer tocompound(s) of the formula I as described above, and their salts,solvates and physiologically functional derivatives as described herein.

The compound(s) of formula (I) may also be administered in combinationwith another active ingredient.

In another preferred embodiment, the invention provides a pharmaceuticalcomposition comprising one or more of the compounds of the instantinvention and at least one other active ingredient. The other activeingredient may comprise one or more antidiabetics, hypoglycemic activeingredients, HMG-CoA reductase inhibitors, cholesterol absorptioninhibitors, PPAR gamma agonists, PPAR alpha agonists, PPAR alpha/gammaagonists, fibrates, MTP inhibitors, bile acid absorption inhibitors,CETP inhibitors, polymeric bile acid adsorbents, LDL receptor inducers,ACAT inhibitors, antioxidants, lipoprotein lipase inhibitors,ATP-citrate lyase inhibitors, squalene synthetase inhibitors,lipoprotein(a) antagonists, lipase inhibitors, insulins, sulfonylureas,biguanides, meglitinides, thiazolidinediones, α-glucosidase inhibitors,active ingredients which act on the ATP-dependent potassium channel ofthe beta cells, CART agonists, NPY agonists, MC4 agonists, orexinagonists, H3 agonists, TNF agonists, CRF agonists, CRF BP antagonists,urocortin agonists, β3 agonists, MSH (melanocyte-stimulating hormone)agonists, CCK agonists, serotonin reuptake inhibitors, mixedserotoninergic and noradrenergic compounds, 5HT agonists, bombesinagonists, galanin antagonists, growth hormones, growth hormone-releasingcompounds, TRH agonists, decoupling protein 2 or 3 modulators, leptinagonists, DA agonists (bromocriptine, Doprexin), lipase/amylaseinhibitors, PPAR modulators, RXR modulators or TR-β agonists oramphetamines.

In another preferred embodiment, the invention provides a process forproducing a pharmaceutical composition comprising one or more of thecompounds of the invention, which comprises mixing the active ingredientwith a pharmaceutically suitable carrier and converting this mixtureinto a form suitable for administration.

In another preferred embodiment, the invention provides a pharmaceuticalcomposition comprising one or more of the compounds of the instantinvention.

In another preferred embodiment, the invention provides a method forreducing blood glucose, comprising administering to a subject in needthereof, one or more compounds of the instant invention.

In another preferred embodiment, the invention provides a method fortreating type 2 diabetes, comprising administering to a subject in needthereof, one or more compounds of the instant invention.

In another preferred embodiment, the invention provides a method fortreating disturbances of lipid and carbohydrate metabolism, comprisingadministering to a subject in need thereof, one or more compounds of theinstant invention.

In another preferred embodiment, the invention provides a method fortreating arteriosclerotic manifestations, comprising administering to asubject in need thereof, one or more compounds of the instant invention.

In another preferred embodiment, the invention provides a method fortreating insulin resistance, comprising administering to a subject inneed thereof, one or more compounds of the instant invention.

The amount of a compound of formula I necessary to achieve the desiredbiological effect depends on a number of factors, for example thespecific compound chosen, the intended use, the mode of administrationand the clinical condition of the patient. The daily dose is generallyin the range from 0.3 mg to 100 mg (typically from 3 mg to 50 mg) perday and per kilogram of bodyweight, for example 3-10 mg/kg/day. Anintravenous dose may be, for example, in the range from 0.3 mg to 1.0mg/kg, which can suitably be administered as infusion of 10 ng to 100 ngper kilogram and per minute. Suitable infusion solutions for thesepurposes may contain, for example, from 0.1 ng to 10 mg, typically from1 ng to 10 mg, per milliliter. Single doses may contain, for example,from 1 mg to 10 g of the active ingredient. Thus, ampoules forinjections may contain, for example, from 1 mg to 100 mg, andsingle-dose formulations which can be administered orally, such as, forexample, capsules or tablets, may contain, for example, from 1.0 to 1000mg, typically from 10 to 600 mg. For the therapy of the abovementionedconditions, the compounds of formula I may be used as the compounditself, but they are preferably in the form of a pharmaceuticalcomposition with an acceptable carrier. The carrier must, of course, beacceptable in the sense that it is compatible with the other ingredientsof the composition and is not harmful for the patient's health. Thecarrier may be a solid or a liquid or both and is preferably formulatedwith the compound as a single dose, for example as a tablet, which maycontain from 0.05% to 95% by weight of the active ingredient. Otherpharmaceutically active substances may likewise be present, includingother compounds of formula 1. The pharmaceutical compositions of theinvention can be produced by one of the known pharmaceutical methods,which essentially consist of mixing the ingredients withpharmacologically acceptable carriers and/or excipients.

Pharmaceutical compositions of the invention are those suitable fororal, rectal, topical, peroral (for example sublingual) and parenteral(for example subcutaneous, intramuscular, intradermal or intravenous)administration, although the most suitable mode of administrationdepends in each individual case on the nature and severity of thecondition to be treated and on the nature of the compound of formula Iused in each case. Coated formulations and coated slow-releaseformulations also belong within the framework of the invention.Preference is given to acid- and gastric juice-resistant formulations.Suitable coatings resistant to gastric juice comprise cellulose acetatephthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulosephthalate and anionic polymers of methacrylic acid and methylmethacrylate.

Suitable pharmaceutical compounds for oral administration may be in theform of separate units such as, for example, capsules, wafers, suckabletablets or tablets, each of which contain a defined amount of thecompound of formula I; as powders or granules, as solution or suspensionin an aqueous or nonaqueous liquid; or as an oil-in-water orwater-in-oil emulsion. These compositions may, as already mentioned, beprepared by any suitable pharmaceutical method which includes a step inwhich the active ingredient and the carrier (which may consist of one ormore additional ingredients) are brought into contact. The compositionsare generally produced by uniform and homogeneous mixing of the activeingredient with a liquid and/or finely divided solid carrier, afterwhich the product is shaped if necessary. Thus, for example, a tabletcan be produced by compressing or molding a powder or granules of thecompound, where appropriate with one or more additional ingredients.Compressed tablets can be produced by tableting the compound infree-flowing form such as, for example, a powder or granules, whereappropriate mixed with a binder, glidant, inert diluent and/or one ormore surface-active/dispersing agent(s) in a suitable machine. Moldedtablets can be produced by molding the compound, which is in powder formand is moistened with an inert liquid diluent, in a suitable machine.The instant invention covers other dosage forms used in the art, forexample, those with micronized or nanosized ingredients.

Pharmaceutical compositions which are suitable for peroral (sublingual)administration comprise suckable tablets which contain a compound offormula I with a flavoring, normally sucrose and gum arabic ortragacanth, and pastilles which comprise the compound in an inert basesuch as gelatin and glycerol or sucrose and gum arabic.

Pharmaceutical compositions suitable for parenteral administrationcomprise preferably sterile aqueous preparations of a compound offormula I, which are preferably isotonic with the blood of the intendedrecipient. These preparations are preferably administered intravenously,although administration may also take place by subcutaneous,intramuscular or intradermal injection. These preparations canpreferably be produced by mixing the compound with water and making theresulting solution sterile and isotonic with blood. Injectablecompositions of the invention generally contain from 0.1 to 5% by weightof the active compound.

Pharmaceutical compositions suitable for rectal administration arepreferably in the form of single-dose suppositories. These can beproduced by mixing a compound of the formula I with one or moreconventional solid carriers, for example cocoa butter, and shaping theresulting mixture.

Pharmaceutical compositions suitable for topical use on the skin arepreferably in the form of ointment, cream, lotion, paste, spray, aerosolor oil. Carriers which can be used are petrolatum, lanolin, polyethyleneglycols, alcohols and combinations of two or more of these substances.The active ingredient is generally present in a concentration of from0.1 to 15% by weight of the composition, for example from 0.5 to 2%.

Transdermal administration is also possible. Pharmaceutical compositionssuitable for transdermal uses can be in the form of single plasterswhich are suitable for long-term close contact with the patient'sepidermis. Such plasters suitably contain the active ingredient in anaqueous solution which is buffered where appropriate, dissolved and/ordispersed in an adhesive or dispersed in a polymer. A suitable activeingredient concentration is about 1% to 35%, preferably about 3% to 15%.A particular possibility is for the active ingredient to be released byelectrotransport or iontophoresis as described, for example, inPharmaceutical Research, 2(6): 318 (1986).

Further active ingredients suitable for combination products are: allantidiabetics mentioned in the Rote Liste 2001, chapter 12. They may becombined with the compounds of the formula I of the invention inparticular for a synergistic improvement of the effect. Administrationof the active ingredient combination may take place either by separateadministration of the active ingredients to the patient or in the formof combination products in which a plurality of active ingredients arepresent in one pharmaceutical preparation. Most of the activeingredients listed below are disclosed in the USP Dictionary of USAN andInternational Drug Names, US Pharmacopeia, Rockville 2001.

Antidiabetics include insulin and insulin derivatives such as, forexample, Lantus® (see www.lantus.com), fast-acting insulins (see U.S.Pat. No. 6,221,633), GLP-1 derivatives such as, for example, thosedisclosed in WO 98/08871 of Novo Nordisk A/S, and orally effectivehypoglycemic active ingredients.

The orally effective hypoglycemic active ingredients include,preferably, sulfonylureas, biguanides, meglitinides,oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors,glucagon antagonists, GLP-1 agonists, potassium channel openers such as,for example, those disclosed in WO 97/26265 and WO 99/03861 of NovoNordisk A/S, insulin sensitizers, inhibitors of liver enzymes involvedin the stimulation of gluconeogenesis and/or glycogenolysis, modulatorsof glucose uptake, compounds which alter lipid metabolism, such asantihyperlipidemic active ingredients and antilipidemic activeingredients, compounds which reduce food intake, PPAR and PXR agonistsand active ingredients which act on the ATP-dependent potassium channelof the beta cells.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with an HMG-CoA reductase inhibitor such assimvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin,cerivastatin, rosuvastatin.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a cholesterol absorption inhibitor suchas, for example, ezetimibe, tiqueside, pamaqueside.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a PPAR gamma agonist, such as, forexample, rosiglitazone, pioglitazone, JTT-501, GI262570

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a PPAR alpha agonist, such as, forexample, GW 9578, GW 7647.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a mixed PPAR alpha/gamma agonist, suchas, for example, GW 1536, AVE 8042, AVE 8134, AVE 0847, or as describedin PCT/US00/11833, PCT/US00/11490, DE10142734.4.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a fibrate such as, for example,fenofibrate, clofibrate, bezafibrate.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with an MTP inhibitor such as, for example,implitapide, BMS-201038, R-103757.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a bile acid absorption inhibitor (see,for example, U.S. Pat. No. 6,245,744 or U.S. Pat. No. 6,221,897).

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a CETP inhibitor, such as, for example,JTT-705.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a polymeric bile acid adsorbent suchas, for example, cholestyramine, colesevelam.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with an LDL receptor inducer (see U.S. Pat.No. 6,342,512).

In one embodiment of the invention, the compounds of the formula I areadministered in combination with an ACAT inhibitor, such as, forexample, avasimibe.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with an antioxidant, such as, for example,OPC-14117.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a lipoprotein lipase inhibitor, suchas, for example, NO-1886.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with an ATP-citrate lyase inhibitor, suchas, for example, SB-204990.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a squalene synthetase inhibitor, suchas, for example, BMS-188494.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a lipoprotein(a) antagonist, such as,for example, CI-1027 or nicotinic acid.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a lipase inhibitor, such as, forexample, orlistat.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with insulin.

In one embodiment, the compounds of the formula I are administered incombination with a sulfonylurea such as, for example, tolbutamide,glibenclamide, glipicide or glimepiride.

In one embodiment, the compounds of the formula I are administered incombination with a biguanide, such as, for example, metformin.

In one further embodiment, the compounds of the formula I areadministered in combination with a meglitinide, such as, for example,repaglinide.

In one embodiment, the compounds of the formula I are administered incombination with a thiazolidinedione, such as, for example,troglitazone, ciglitazone, pioglitazone, rosiglitazone or the compoundsdisclosed in WO 97/41097 of Dr. Reddy's Research Foundation, inparticular5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidinedione.

In one embodiment, the compounds of the formula I are administered incombination with an α-glucosidase inhibitor, such as, for example,miglitol or acarbose.

In one embodiment, the compounds of the formula I are administered incombination with an active ingredient which acts on the ATP-dependentpotassium channel of the beta cells, such as, for example, tolbutamide,glibenclamide, glipicide, glimepiride or repaglinide.

In one embodiment, the compounds of the formula I are administered incombination with more than one of the aforementioned compounds, e.g. incombination with a sulfonylurea and metformin, with a sulfonylurea andacarbose, repaglinide and metformin, insulin and a sulfonylurea, insulinand metformin, insulin and troglitazone, insulin and lovastatin, etc.

In a further embodiment, the compounds of the formula I are administeredin combination with CART modulators (see “Cocaine-amphetamine-regulatedtranscript influences energy metabolism, anxiety and gastric emptying inmice” Asakawa, A, et al., in: Hormone and Metabolic Research (2001),33(9), 554-558), NPY antagonists, e.g. naphthalene-1-sulfonic acid{4-[(4-aminoquinazolin-2-ylamino)methyl] cyclohexylmethyl}amidehydrochloride (CGP 71683A)), MC4 agonists (e.g.1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid[2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydropyrazolo[4,3-c]pyridin-5-yl)-1-(4-chlorophenyl)-2-oxoethyl]-amide;(WO 01/91752)), orexin antagonists (e.g.1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-ylurea hydrochloride(SB-334867-A)), H3 agonists(3-cyclohexyl-1-(4,4-dimethyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)propan-1-oneoxalic acid salt (WO 00/63208)); TNF agonists, CRF antagonists (e.g.[2-methyl-9-(2,4,6-trimethylphenyl)-9H-1,3,9-triazafluoren-4-yl]dipropylamine(WO 00/66585)), CRF BP antagonists (e.g. urocortin), urocortin agonists,β3 agonists (e.g.1-(4-chloro-3-methanesulfonylmethylphenyl)-2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]-ethanol hydrochloride (WO 01/83451)), MSH(melanocyte-stimulating hormone) agonists, CCK-A agonists (e.g.{2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)thiazol-2-ylcarbamoyl]-5,7-dimethylindol-1-yl}aceticacid trifluoroacetic acid salt (WO 99/15525)), serotonin reuptakeinhibitors (e.g. dexfenfluramine), mixed serotoninergic andnoradrenergic compounds (e.g. WO 00/71549), 5 HT agonistse.g.1-(3-ethylbenzofuran-7-yl)piperazine oxalic acid salt (WO 01/09111),bombesin agonists, galanin antagonists, growth hormone (e.g. humangrowth hormone), growth hormone-releasing compounds(6-benzyloxy-1-(2-diisopropylaminoethylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tertiary butyl ester (WO 01/85695)),TRH agonists (see, for example, EP 0 462 884), decoupling protein 2 or 3modulators, leptin agonists (see, for example, Lee, Daniel W.; Leinung,Matthew C.; Rozhavskaya-Arena, Marina; Grasso, Patricia. Leptin agonistsas a potential approach to the treatment of obesity. Drugs of the Future(2001), 26(9), 873-881), DA agonists (bromocriptine, Doprexin),lipase/amylase inhibitors (e.g. WO 00/40569), PPAR modulators (e.g. WO00/78312), RXR modulators or TR-β agonists.

In one embodiment of the invention, the other active ingredient isleptin; see, for example, “Perspectives in the therapeutic use ofleptin”, Salvador, Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema, ExpertOpinion on Pharmacotherapy (2001), 2(10), 1615-1622.

In one embodiment, the other active ingredient is dexamphetamine oramphetamine.

In one embodiment, the other active ingredient is fenfluramine ordexfenfluramine.

In another embodiment, the other active ingredient is sibutramine.

In one embodiment, the other active ingredient is orlistat.

In one embodiment, the other active ingredient is mazindol orphentermine.

In one embodiment, the compounds of the formula I are administered incombination with bulking agents, preferably insoluble bulking agents(see, for example, carob/Caromax® (Zunft H J; et al., Carob pulppreparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY(2001 September-October), 18(5), 230-6.) Caromax is a carob-containingproduct from Nutrinova, Nutrition Specialties & Food Ingredients GmbH,Industriepark Höchst, 65926 Frankfurt/Main)). Combination with Caromax®is possible in one preparation or by separate administration ofcompounds of the formula I and Caromax®. Caromax® can in this connectionalso be administered in the form of food products such as, for example,in bakery products or muesli bars.

It will be appreciated that every suitable combination of the compoundsof the invention with one or more of the aforementioned compounds andoptionally one or more other pharmacologically active substances isregarded as falling within the protection conferred by the presentinvention. The following compounds are exemplary pharmaceuticalsubstances that may be used in combination with the instant compounds.

The examples detailed below serve to illustrate the invention, butwithout restricting it.

TABLE 1 Examples of the formula I

Ex. R9, R10, R11, R12 R3 R4 R5 R6 Linkage R8 MS* 1 2-Cl-4,5-F₂ 2-H 4-H5-H 6-OCH₃ 3 NHCH₃ ok 2 2-Cl-4,5-F₂ 2-H 4-COOC₂H₅ 5-H 6-OCH₃ 3 NHCH₃ ok3 2-Cl-4-F 2-H 3-COOH 4-H 5-H 6 OCH₃ ok 4 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-OCF₃3 NHC₂H₅ ok 5 2-Cl-4,5-F₂ 2-H 4-H 5-H

3 NHC₂H₅ ok 6 2-Cl-4,5-F₂ 2-H 4-H 5-H

3 NHC₂H₅ ok 7 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-N(CH₃)₂ 3 NHC₂H₅ ok 82-Cl-4,5-F₂ 2-H 4-H 5-H

3 NHC₂H₅ ok 9 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-Cl 3 NHC₂H₅ ok 10 2-Cl-4,5-F₂2-H 4-H 5-H 6-OCH₃ 3 NHC₂H₅ ok 11 2-Cl-4,5-F₂ 2-H 4-COOC₂H₅ 5-H 6-OCH₃ 3NHC₂H₅ ok 12 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-OCH₃ 3

ok 13 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-OCH₃ 3

ok 14 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-OCH₃ 3

ok 15 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-OCH₃ 3

ok 16 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-OCH₃ 3

ok 17 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-OCH₃ 3

ok 18 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-OCH₃ 3 NHCH₂COOC₂H₅ ok 19 2-Cl-4,5-F₂2-H 4-H 5-H 6-OCH₃ 3

ok 20 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-OCH₃ 3

ok 21 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-OCH₃ 3

ok 22 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-OCH₃ 3

ok 23 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-OCH₃ 3

ok 24 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-OCH₃ 3

ok 25 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-OCH₃ 3

ok 26 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-OCH₃ 3

ok 27 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-OCH₃ 3 NH(CH₂)₃CH₃ ok 28 2-Cl-4,5-F₂ 2-H4-H 5-H 6-OCH₃ 3

ok 29 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-OCH₃ 3

ok 30 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-OCH₃ 3 NHCH(CH₃)₂ ok 31 2-Cl-4,5-F₂ 2-H4-H 5-H 6-OCH₃ 3 NH(CH₂)₅CH₃ ok 32 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-OCH₃ 3

ok 33 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-OCH₃ 3

ok 34 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-OCH₃ 3

ok 35 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-OCH₃ 3 NH(CH₂)₂CH₃ ok 36 2-Cl-4,5-F₂ 2-H4-H 5-H 6-OCH₃ 3

ok 37 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-OCH₃ 3

ok 38 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-OCH₃ 3

ok 39 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-OCH₃ 3

ok 40 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-OCH₃ 3

ok 41 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-OCH₃ 3

ok 42 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-OCH₃ 3

ok 43 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-OCH₃ 3 NH(CH₂)₄CH₃ ok 44 2-Cl-4,5-F₂ 2-H4-H 5-H 6-OCH₃ 3

ok 45 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-OCH₃ 3

ok 46 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-OCH₃ 3

ok 47 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-OCH₃ 3

ok 48 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-OCH₃ 3 NH(CH₂)₂COOC₂H₅ ok 49 2-Cl-4,5-F₂2-H 4-H 5-H 6-OCH₃ 3

ok 50 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-OCH₃ 3

ok 51 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-OCH₃ 3

ok 52 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-OCH₃ 3

ok 53 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-OCH₃ 3

ok 54 2-Cl-4,5-F₂ 2-H 4-H 5-H

3

ok 55 2-Cl-4,5-F₂ 2-H 4-H 5-H

3

ok 56 2-Cl-4,5-F₂ 2-H 4-H 5-H

3

ok 57 2-Cl-4,5-F₂ 2-H 4-H 5-H

3

ok 58 2-Cl-4,5-F₂ 2-H 4-H 5-H

3

ok 59 2-Cl-4,5-F₂ 2-H 4-H 5-H

3 NHCH₂COOC₂H₅ ok 60 2-Cl-4,5-F₂ 2-H 4-H 5-H

3

ok 61 2-Cl-4,5-F₂ 2-H 4-H 5-H

3

ok 62 2-Cl-4,5-F₂ 2-H 4-H 5-H

3

ok 63 2-Cl-4,5-F₂ 2-H 4-H 5-H

3

ok 64 2-Cl-4,5-F₂ 2-H 4-H 5-H

3

ok 65 2-Cl-4,5-F₂ 2-H 4-H 5-H

3

ok 66 2-Cl-4,5-F₂ 2-H 4-H 5-H

3

ok 67 2-Cl-4,5-F₂ 2-H 4-H 5-H

3

ok 68 2-Cl-4,5-F₂ 2-H 4-H 5-H

3 NH(CH₂)₃CH₃ ok 69 2-Cl-4,5-F₂ 2-H 4-H 5-H

3

ok 70 2-Cl-4,5-F₂ 2-H 4-H 5-H

3

ok 71 2-Cl-4,5-F₂ 2-H 4-H 5-H

3 NHCH(CH₃)₂ ok 72 2-Cl-4,5-F₂ 2-H 4-H 5-H

3 NH(CH₂)₅CH₃ ok 73 2-Cl-4,5-F₂ 2-H 4-H 5-H

3

ok 74 2-Cl-4,5-F₂ 2-H 4-H 5-H

3

ok 75 2-Cl-4,5-F₂ 2-H 4-H 5-H

3 NH(CH₂)₂CH₃ ok 76 2-Cl-4,5-F₂ 2-H 4-H 5-H

3

ok 77 2-Cl-4,5-F₂ 2-H 4-H 5-H

3

ok 78 2-Cl-4,5-F₂ 2-H 4-H 5-H

3

ok 79 2-Cl-4,5-F₂ 2-H 4-H 5-H

3

ok 80 2-Cl-4,5-F₂ 2-H 4-H 5-H

3

ok 81 2-Cl-4,5-F₂ 2-H 4-H 5-H

3

ok 82 2-Cl-4,5-F₂ 2-H 4-H 5-H

3

ok 83 2-Cl-4,5-F₂ 2-H 4-H 5-H

3 NH(CH₂)₄CH₃ ok 84 2-Cl-4,5-F₂ 2-H 4-H 5-H

3

ok 85 2-Cl-4,5-F₂ 2-H 4-H 5-H

3

ok 86 2-Cl-4,5-F₂ 2-H 4-H 5-H

3

ok 87 2-Cl-4,5-F₂ 2-H 4-H 5-H

3

ok 88 2-Cl-4,5-F₂ 2-H 4-H 5-H

3 NH(CH₂)₂COOC₂H₅ ok 89 2-Cl-4,5-F₂ 2-H 4-H 5-H

3

ok 90 2-Cl-4,5-F₂ 2-H 4-H 5-H

3

ok 91 2-Cl-4,5-F₂ 2-H 4-H 5-H

3

ok 92 2-Cl-4,5-F₂ 2-H 4-H 5-H

3

ok 93 2-Cl-4,5-F₂ 2-H 4-H 5-H

3

ok 94 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-OCHF₂ 3 OCH₃ ok 95 2-Cl-4,5-F₂ 2-H 4-H5-H 6-OCHF₂ 3 NHC₂H₅ ok 96 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-OCH₃ 3 O(CH₂)₂CH₃ok 97 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-OCH₃ 3

ok 98 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-OCH₃ 3 O(CH₂)₃CH₃ ok 99 2-Cl-4,5-F₂ 2-H4-H 5-H 6-OCH₃ 3 OCH₂CH(CH₃)₂ ok 100 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-OCH₃ 3OC₂H₅ ok 101 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-OCH₃ 3 OCH₂C≡CCH₃ ok 1022-Cl-4,5-F₂ 2-H 4-H 5-H 6-OCH₃ 3

ok 103 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-OCH₃ 3 O(CH₂)₂CH═CH₂ ok 104 2-Cl-4,5-F₂2-H 4-H 5-H 6-OCH₃ 3 O(CH₂)₅CH₃ ok 105 2-Cl-4,5-F₂ 2-H 4-H 5-H

3 O(CH₂)₂CH₃ ok 106 2-Cl-4,5-F₂ 2-H 4-H 5-H

3

ok 107 2-Cl-4,5-F₂ 2-H 4-H 5-H

3 O(CH₂)₃CH₃ ok 108 2-Cl-4,5-F₂ 2-H 4-H 5-H

3 OCH₂CH(CH₃)₂ ok 109 2-Cl-4,5-F₂ 2-H 4-H 5-H

3 OC₂H₅ ok 110 2-Cl-4,5-F₂ 2-H 4-H 5-H

3

ok 111 2-Cl-4,5-F₂ 2-H 4-H 5-H

3 OCH₂C≡CCH₃ ok 112 2-Cl-4,5-F₂ 2-H 4-H 5-H

3

ok 113 2-Cl-4,5-F₂ 2-H 4-H 5-H

3 O(CH₂)₂CH═CH₂ ok 114 2-Cl-4,5-F₂ 2-H 4-H 5-H

3 O(CH₂)₅CH₃ ok 115 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-OC₂H₅ 3 OCH₃ ok 1162-Cl-4,5-F₂ 2-H 4-H 5-H 6-OC₂H₅ 3 NHC₂H₅ ok 117 2-Cl-4,5-F₂ 2-H 4-H 5-H6-O(CH₂)₂CH₃ 3 OCH₃ ok 118 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-O(CH₂)₂CH₃ 3 NHC₂H₅ok 119 2-Cl-4,5-F₂ 2-H 4-H 5-H 6-O(CH₂)₃CH₃ 3 OCH₃ ok 120 2-Cl-4,5-F₂2-H 4-H 5-H 6-O(CH₂)₃CH₃ 3 NHC₂H₅ ok 121 2-Cl-4,5-F₂ 2-H 4-H 5-H

3 OCH₃ ok 122 2-Cl-4,5-F₂ 2-H 4-H 5-H

3 NHC₂H₅ ok 123 2-Cl-4,5-F₂ 2-H 4-H 5-H

3 OCH₃ ok 124 2-Cl-4,5-F₂ 2-H 4-H 5-H

3 NHC₂H₅ ok 125 2,4-Cl₂ 2-H 4-H 5-H 6-H 3 NHCH₃ ok 126 2,4-Cl₂ 2-H 4-H5-H 6-Cl 3 NHCH₃ ok 127 2,4-Cl₂ 2-H 4-H 5-H 6-OCH₃ 3 NHCH₃ ok 1282,4-Cl₂ 2-H 4-H 5-H 6-OCH₃ 3 NH(CH₂)₂COOC₂H₅ ok 129 2-Cl-4,5-F₂ 2-H 4-H5-H 6-Cl 3 NHCH₃ ok 130 2,4-Cl₂ 2-H 3-H 5-H 6-H 4 NHCH₃ ok 131 2,4-Cl₂2-H 3-H 5-H 6-H 4 NH(CH₂)₃NH₂ × TFA ok 132 2-Cl-4,5-F₂ 2-H — 5-H 6-OCH₃3

ok *The statement “MS is ok” means that a mass spectrum or HPLC/MS wasrecorded and the molecular peak (molecular mass + H⁺) was detectedtherein.

The compounds of the formula I are distinguished by beneficial effectson glucose metabolism; in particular they lower the blood glucose leveland are suitable for the treatment of type 2 diabetes. The compounds cantherefore be employed alone or in combination with other bloodglucose-lowering active ingredients (antidiabetics).

The compounds of the formula I are further suitable for the treatment oflate complications of diabetes such as, for example, nephropathy,retinopathy, neuropathy and myocardial infarction, peripheral arterialocclusive diseases, thromboses, arteriosclerosis, syndrome X, obesity,inflammations, immune diseases, autoimmune diseases such as, forexample, AIDS, asthma, osteoporosis, cancer, psoriasis, Alzheimer's,schizophrenia and infectious diseases.

The activity of the compounds was assayed as follows:

Glycogen Phosphorylase a Activity Assay

The effect of compounds on the activity of the active form of glycogenphosphorylase (GPa) was measured in the reverse direction by followingthe synthesis of glycogen from glucose 1-phosphate by determining theliberation of inorganic phosphate. All the reactions were carried out asduplicate determinations in microtiter plates with 96 wells (Half AreaPlates, Costar No 3696), measuring the change in absorption owing to theformation of the reaction product at the wavelength specifiedhereinafter in a Multiskan Ascent Elisa Reader (Lab Systems, Finland).In order to measure the GPa enzymic activity in the reverse direction,the general method of Engers et al. (Engers H D, Shechosky S, Madsen NB, Can J Biochem 1970 July; 48(7):746-754) was used to measure theconversion of glucose 1-phosphate into glycogen and inorganic phosphate,with the following modifications: human glycogen phosphorylase a (forexample with 0.76 mg of protein/ml (Aventis Pharma Deutschland GmbH),dissolved in buffer solution E (25 mM β-glycerophosphate, pH 7.0, 1 mMEDTA and 1 mM dithiothreitol) was diluted with buffer T (50 mM hepes, pH7.0, 100 mM KCl, 2.5 mM EDTA, 2.5 mM MgCl₂6H₂O) and addition of 5 mg/mlglycogen to a concentration of 10 μg of protein/ml. Test substances wereprepared as 10 mM solution in DMSO and diluted to 50 μM with buffersolution T. To 10 μl of this solution were added 10 μl of 37.5 mMglucose, dissolved in buffer solution T, and 5 mg/ml glycogen, plus 10μl of a solution of human glycogen phosphorylase a (10 μg of protein/ml)and 20 μl of glucose 1-phosphate, 2.5 mM. The baseline glycogenphosphorylase a activity in the absence of test substance was determinedby adding 10 μl of buffer solution T (0.1% DMSO). The mixture wasincubated at room temperature for 40 minutes, and the liberated organicphosphate was measured by the general method of Drueckes et al.(Drueckes P, Schinzel R, Palm D, Anal Biochem 1995 Sep. 1;230(1):173-177) with the following modifications: 50 μl of a stopsolution of 7.3 mM ammonium molybdate, 10.9 mM zinc acetate, 3.6%ascorbic acid, 0.9% SDS are added to 50 μl of the enzyme mixture. Afterincubation at 45° C. for 60 minutes, the absorption at 820 nm wasmeasured. To determine the background absorption, in a separate mixturethe stop solution was added immediately after addition of the glucose1-phosphate solution. This test was carried out with a concentration of10 μM of the test substance in order to determine the particularinhibition of glycogen phosphorylase a in vitro by the test substance.

TABLE 2 Biological activity % inhibition Ex. at 10 μM 2 96 3 53 4 89 7100 13 103 14 70 21 75 26 61 42 55 44 40 65 60 76 73 90 89 91 99 92 78104 66 108 52 110 73 113 83 114 48 121 99 125 74 127 102 130 28 132 97

It is evident from the table that the compounds of the formula I inhibitthe activity of glycogen phosphorylase a and thus are very suitable forlowering the blood glucose level. They are therefore particularlysuitable for the prevention and treatment of type 2 diabetes.

The preparation of some examples is described in detail below, and theother compounds of the formula I were obtained analogously:

EXPERIMENTAL PART

The numbering of the following examples corresponds to the tables above.

Example 11-{3-[3-(2-Chloro-4,5-difluorobenzoyl)ureido]-4-methoxyphenyl}-3-methylurea

a) 2-Chloro-4,5-difluorobenzoyl isocyanate

2-Chloro-4,5-difluorobenzamide was dissolved in dichloromethane, mixedwith 1.5 eq. of oxalyl chloride and heated to reflux for 16 hours. Thereaction mixture was concentrated under high vacuum and employed instage b without further purification.

b) 1-(2-Chloro-4,5-difluorobenzoyl)-3-(2-methoxy-5-nitrophenyl)urea

4.0 g (23.8 mmol) of 2-methoxy-5-nitroaniline were dissolved in 10 ml ofN-methyl-2-pyrrolidinone, and 5.2 g (23.8 mmol) of2-chloro-4,5-difluorobenzoyl isocyanate were added. Slight warmingoccurred. After 15 minutes at room temperature, diethyl ether was added,and the resulting precipitate was filtered off with suction. 6.6 g (79%)of the desired product were obtained.

c) 1-(5-Amino-2-methoxyphenyl)-3-(2-chloro-4,5-difluorobenzoyl)urea

5.8 g (25.9 mmol) of tin dichloride hydrate were added to 2.0 g (5.2mmol) of1-(2-chloro-4,5-difluorobenzoyl)-3-(2-methoxy-5-nitrophenyl)urea in 20ml of ethyl acetate/methanol mixture at 70° C. After 1 hour, 30 ml ofN-methyl-2-pyrrolidinone were added, and the mixture was stirred for afurther 2 hours. After cooling, the reaction mixture was made basic andthe resulting precipitate was filtered off with suction. The phases wereseparated. The organic phase was then washed three times with water,dried and concentrated under high vacuum. 1.2 g (67%) of the desiredproduct were obtained.

d)1-{3-[3-(2-Chloro-4,5-difluorobenzoyl)ureido]-4-methoxyphenyl}-3-methylurea

600 mg (1.7 mmol) of1-(5-amino-2-methoxyphenyl)-3-(2-chloro-4,5-difluoro-benzoyl)urea weredissolved in 5 ml of acetonitrile, and 69 mg (1.7 mmol) of methylisocyanate were added. After stirring at room temperature for one hour,the resulting precipitate was filtered off with suction. 638 mg (91%) ofthe desired product were obtained.

Example 33-[3-(2-Chloro-4-fluorobenzoyl)ureido]-4-methoxycarbonylaminobenzoicacid

a) 2-Chloro-4-fluorobenzoyl isocyanate

1.64 g (6 mmol) of 2-chloro-4-fluorobenzamide were dissolved in 3 ml ofdichloromethane and, at 0° C. and under a nitrogen atmosphere, 0.8 ml(9.3 mmol) of oxalyl chloride was added, and the mixture was heated toreflux for 9 hours. The reaction mixture was concentrated under highvacuum and afforded 1.17 g (5.8 mmol) of the desired product, which wasemployed as solution in dichloromethane (1 mmol in 1.7 ml of solution)in stage b.

b) 4-Amino-3-[3-(2-chloro-4-fluorobenzoyl)ureido]benzoic acid

150 mg (1 mmol) of 3,4-diaminobenzoic acid were dissolved in 2 ml ofN-methyl-2-pyrrolidinone and, at 0° C., 1 ml (1.2 mmol) of the2-chloro-4-fluorobenzoyl isocyanate/dichloromethane solution prepared instage a was added. The resulting precipitate was filtered off withsuction. The crude mixture (500 mg) was purified by columnchromatography (dichloromethane/methanol=98/2 to 93/7). 80 mg (25%) ofthe desired product were obtained.

c) 3-[3-(2-Chloro-4-fluorobenzoyl)ureido]-4-methoxycarbonylaminobenzoicacid SA-2919

28 mg (0.08 mmol) of4-amino-3-[3-(2-chloro-4-fluorobenzoyl)ureido]benzoic acid weredissolved in 0.5 ml of N-methyl-2-pyrrolidinone and stirred with 0.02 ml(0.24 mmol) of pyridine and 0.007 ml of methyl chloroformate at roomtemperature for 4 hours. Water and acetic acid were added, and theresulting precipitate was filtered off with suction. 18 mg (55%) of thedesired product were obtained.

Melting point: decomposition >400° C.

Example 54 Methyl3-{2-[3-(2-chloro-4,5-difluorobenzoyl)ureido]-4-[3-(2-trifluoromethylphenyl)-ureido]phenyl}acrylate

a) Methyl3-{2-[3-(2-chloro-4,5-difluorobenzoyl)ureido]-4-nitrophenyl}acrylateF-33579-057

4.5 g (20.3 mmol) of methyl 3-(2-amino-4-nitrophenyl)acrylate werestirred with 4.41 g (20.3 mmol) of 2-chloro-4,5-difluorobenzoylisocyanate (Example 1a) in 50 ml acetonitrile at 50° C. for one hour.The reaction mixture was then concentrated, the residue was stirred withdiethyl ether, and the resulting solid was filtered off with suction.8.5 g (95%) of the desired product were obtained.

b) Methyl3-{4-amino-2-[3-(2-chloro-4,5-difluorobenzoyl)ureido]phenyl}acrylate

8.5 g (19.3 mmol) of methyl3-{2-[3-(2-chloro-4,5-difluorobenzoyl)ureido]-4-nitro-phenyl}acrylatewere suspended in 60 ml of a mixture of glacial acetic acid andconcentrated hydrochloric acid (10:1) and heated to 70° C. Then 8.85 g(135.3 mmol) of zinc powder were added. After 30 minutes, the mixturewas cooled, the solid was filtered off with suction, and the filtratewas concentrated. The residue was taken up in ethyl acetate and washedwith a 10% strength sodium bicarbonate solution. The organic phase wasdried and concentrated. 7.9 g (100%) of the desired product wereobtained.

c) Methyl3-{2-[3-(2-chloro-4,5-difluorobenzoyl)ureido]-4-[3-(2-trifluoromethyl-phenyl)ureido]phenyl}acrylate

100 mg (0.24 mmol) of methyl3-{4-amino-2-[3-(2-chloro-4,5-difluorobenzoyl)-ureido]phenyl}acrylatewere dissolved in 1 ml of acetonitrile and mixed with2-trifluoromethylphenyl isocyanate and shaken at 60° C. for 14 hours.The resulting precipitate was filtered off with suction, and 16 mg (11%)of the desired product were obtained.

Example 110 Methyl(E)-3-[2-[3-(2-chloro-4,5-difluorobenzoyl)ureido]-4-(4-chloro-phenoxycarbonylamino)phenyl]acrylate

100 mg (0.24 mmol) of methyl3-{4-amino-2-[3-(2-chloro-4,5-difluorobenzoyl)-ureido]phenyl}acrylate(example 54 b) were reacted in 2 ml of dimethylformamide with potassiumcarbonate and 4-chlorophenyl chloroformate. The precipitate resultingafter 4 hours was filtered off with suction. Preparative HPLC (column:Waters Xterra™MS C₁₈, 5 μm, 30×100 mm, mobile phases: A: H₂O+0.2%trifluoroacetic acid, B: acetonitrile, gradient: 2.5 minutes 90% A/10% Bto 17.5 minutes 10% A/90% B) resulted in 12 mg (9%) of the desiredproduct.

Example 1321-(2-Chloro-4,5-difluorobenzoyl)-3-(6-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-yl)urea

a) N-(4-Methoxy-2-methylphenyl)acetamide

41.1 g (0.3 mol) of 4-methoxy-2-methylphenylamine and 37 g (0.5 mol) ofdimethylethylamine were dissolved in 50 ml of tetrahydrofuran, and 35.7g (0.35 mol) of acetic anhydride were added while stirring. The solutionheated to boiling during this. It was stirred at room temperature for 1hour and cooled to 0° C. The resulting precipitate was filtered off withsuction and washed several times with a little cold tetrahydrofuran anddried. 40 g (75%) of colorless crystals of the desired product wereobtained.

b) N-(4-Methoxy-2-methyl-5-nitrophenyl)acetamide

34 g(0.19 mol) of N-(4-methoxy-2-methylphenyl)acetamide were added insmall portions to a mixture of 40 ml of glacial acetic acid and 70 ml offuming nitric acid at −10 to −15° C. These portions were such that thetemperature did not rise above −10° C. The reaction mixture was thenpoured onto ice. The resulting precipitate was filtered off with suctionand washed with water, ethanol and diethyl ether. 22.5 g (53%) of thedesired product were obtained.

c) 2-Acetylamino-5-methoxy-4-nitrobenzoic acid

11.2 g (50 mmol) of N-(4-methoxy-2-methyl-5-nitrophenyl)acetamide and8.5 g (62.5 mmol) of anhydrous magnesium sulfate were suspended in 500ml of water and heated to 85° C. Over the course of 30 minutes, asolution of 21.8 g (138 mmol) of potassium permanganate in 250 ml ofwater was added dropwise. The reaction mixture was stirred at 85° C. for3 hours and then filtered hot to remove manganese dioxide. The latterwas extracted by boiling three times with 100 ml of water each time. Thecombined aqueous phases were again filtered hot and concentrated toabout 150 ml in vacuo. The residue was acidified to pH 1-2 withconcentrated hydrochloric acid and cooled to 0° C. The resulting productwas filtered off with suction, washed with water and diethyl ether,dried and reacted without further purification in the next stage.

d) 2-Amino-5-methoxy-4-nitrobenzoic acid

7.5 g of 2-acetylamino-5-methoxy-4-nitrobenzoic acid (crude mixture fromstage c) were heated to reflux in 50 ml of water and 20 ml ofconcentrated hydrochloric acid for 3 hours. The reaction mixture wasconcentrated in vacuo and purified by column chromatography (silica gel,dichloromethane/isopropanol =9/1). 3.1 g (50%) of the desired productwere obtained.

e) 6-Methoxy-7-nitro-1 H-benzo[d][1,3]oxazine-2,4-dione

2.0 g (9.4 mmol) of 2-amino-5-methoxy-4-nitrobenzoic acid were dissolvedin 20 ml of chloroform and 10 ml of tetrahydrofuran, and 20 ml of 20%strength phosgene solution (1.8 M in toluene) were added. After 3 hoursunder reflux, a further 10 ml of phosgene solution were added at 60° C.,and the mixture was stirred at 60° C. for a further 12 hours. Thephosgene was distilled off and the residue was concentrated in vacuoafter addition of toluene several times. 2.2 g (100%) of the desiredproduct were obtained.

f) 2-Amino-5-methoxy-4-nitrobenzamide

476 mg (2 mmol) of 6-methoxy-7-nitro-1H-benzo[d][1,3]oxazine-2,4-dioneand 1.5 g (20 mmol) of ammonium acetate were dissolved in 20 ml ofacetic acid and heated at 105° C. for 3 hours. The reaction mixture wasthen poured into ice-water and slowly brought to pH 7 with solid sodiumbicarbonate. The aqueous phase was extracted with ethyl acetate. Theorganic phase was washed with water, dried and concentrated in vacuo.The crude product was triturated with diethyl ether, and the resultingprecipitate was filtered off with suction. 285 mg (68%) of the desiredproduct were obtained.

g) 6-Methoxy-7-nitro-1H-quinazoline-2,4-dione

108 mg (0.5 mmol) of 2-amino-5-methoxy-4-nitrobenzamide were dissolvedin 5 ml of tetrahydrofuran and 5 ml of chloroform, and oxalyl chloride(solution in toluene) was added. The mixture was stirred at 60° C. for 5hours and then concentrated in vacuo. Addition of toluene was followedby renewed concentration. 120 mg (100%) of the desired product wereobtained.

h) 7-Amino-6-methoxy-1H-quinazoline-2,4-dione

120 mg (0.5 mmol) of 6-methoxy-7-nitro-1H-quinazoline-2,4-dione weretaken up in a mixture of 5 ml of tetrahydrofuran, 5 ml of methanol and 5ml of acetic acid and hydrogenated with palladium catalysis at roomtemperature for 3 hours. The reaction solution was heated to dissolveprecipitated product and was filtered hot to remove the catalyst. Thefiltrate was concentrated and, after addition of toluene, againconcentrated. 100 mg (100%) of the desired product were obtained.

i)1-(2-Chloro-4,5-difluorobenzoyl)-3-(6-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-yl)urea

100 mg (0.53 mmol) of 7-amino-6-methoxy-1H-quinazoline-2,4-dione weresuspended in 20 ml of acetonitrile and 2 ml of N-methyl-2-pyrrolidinone,and 200 mg (0.97 mmol) of 2-chloro-4,5-difluorobenzoyl isocyanate(example 1a) were added. The reaction mixture was heated to boiling andthen quenched with methanol and concentrated in vacuo. The residue wasstirred with acetonitrile, and the resulting precipitate was filteredoff. 64 mg (30%) of the desired product were obtained.

All documents referred to herein are incorporated herein by reference intheir entirety, including the priority documents, DE 10231371.7-42 filedJul. 11, 2002, and U.S. Provisional No.60/425,600, filed Nov. 12, 2002.

1. A compound of the formula 1,

in which W, X, Y are, independently of one another, O or S; R9, R10,R11, R12 are, independently of one another, H, F, Cl, Br, OH, CF₃, NO₂,CN, OCF₃, O—(C₁-C₆)-alkyl, O—(C₂-C₆)-alkenyl, O—(C₂-C₆)-alkynyl,O—SO₂—(C₁-C₄)-alkyl, O—SO₂-phenyl, where the phenyl ring may besubstituted up to twice by F, Cl, Br, CN, OR13, R13, CF₃, OCF₃, COOR13or CON(R14)(R15), S—(C₁-C₆)-alkyl, S—(C₂-C₆)-alkenyl, S—(C₂-C₆)-alkynyl,SO—(C₁-C₆)-alkyl, SO₂—(C₁-C₆)-alkyl, SO₂—NH₂, (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl, —COOR13, (C₁-C₆)-alkylene-COOR13,CON(R14)(R15), —N(R14)(R15), (C₁-C₆)-alkylene-N(R14)(R15), NH—COR13,NH—CO-phenyl, or NH—SO₂-phenyl or phenyl, where the phenyl ring may besubstituted up to twice by F, Cl, Br, CN, OR13, R13, CF₃, OCF₃, COOR13or CON(R14)(R15); R13 is H, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,(C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl or (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl;R1, R2 are, independently of one another, H, (C₁-C₆)-alkyl, where alkylmay be substituted by OH, O—(C₁-C₄)-alkyl, N(R14)(R15), O—(C₁-C₆)-alkyl,O—(C₂-C₆)-alkenyl, O—(C₂-C₆)-alkynyl, CO—(C₁-C₆)-alkyl,CO—(C₂-C₆)-alkenyl, CO—(C₂-C₆)-alkynyl, COOR13 or(C₀-C₆)-alkylene-COOR13; R3, R4, R5, R6 are, independently of oneanother, H, F, Cl, Br, OH, CF₃, NO₂, CN, OCF₃, (C₂-C₆)-alkyl,(C₂-C₆)-alkenyl, O—(C₁-C₁₀)-alkyl, O—(C₂-C₁₀)-alkenyl,O—(C₂-C₁₀)-alkynyl, S—(C₁-C₆)-alkyl, S—(C₂-C₆)-alkenyl,S—(C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl,where alkyl, alkenyl, alkynyl and cycloalkyl may be substituted one ormore times by F, Cl, Br, SO-phenyl, SO₂-phenyl, where the phenyl ringmay be substituted by F, Cl, Br or R13, or OR13, COOR13, CON(R14)(R15),N(R14)(R15) or CO-heteroalkyl, or are O—SO—(C₁-C₆)-alkyl,O—SO₂—(C₁-C₆)-alkyl, O—SO₂—(C₆-C₁₀)-aryl, O—(C₆-C₁₀)-aryl, where arylmay be substituted up to twice by F, Cl, CN, OR13, R13, CF₃ or OCF₃, orare SO—(C₁-C₆)-alkyl, SO₂—(C₁-C₆)-alkyl, SO₂—(C₆-C₁₀)-aryl, where thephenyl ring may be substituted up to twice by F, Cl, Br, CN, OR13, R13,CF₃, OCF₃, COOR13 or CON(R14)(R15), or are SO₂—N(R14)(R15), COOR13,CO-heteroalkyl, N(R14)(R15) or heteroalkyl; R14, R15 are, independentlyof one another, H, (C₁-C₆)-alkyl, where alkyl may be substituted byN(R13)₂, or are (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl, CO—(C₁-C₆)-alkyl, COO—(C₁-C₆)-alkyl,COO—(C₁-C₆)-alkylene-OCO—(C₁-C₆)-alkyl, CO-phenyl, COO-phenyl,COO—(C₁-C₆)-alkenyl-phenyl, OH, O—(C₁-C₆)-alkyl,O—(C₁-C₆)-alkenyl-phenyl or NH₂; or the radicals R14 and R15 form withthe nitrogen atom to which they are bonded a 3-7-membered, saturatedheterocyclic ring which may comprise up to 2 further heteroatoms fromthe group of N, O or S, where the heterocyclic ring may be substitutedup to three times by F, Cl, Br, OH, oxo, N(R16)(R17) or (C₁-C₄)-alkyl;R16, R17 are, independently of one another, H, (C₁-C₆)-alkyl, wherealkyl may be substituted by N(R13)₂, or are (C₂-C₆)-alkenyl,(C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl,CO—(C₁-C₆)-alkyl, COO—(C₁-C₆)-alkyl,COO—(C₁-C₆)-alkylene-OCO—(C₁-C₆)-alkyl, CO-phenyl, COO-phenyl,COO—(C₁-C₆)-alkenyl-phenyl, OH, O—(C₁-C₆)-alkyl,O—(C₁-C₆)-alkenyl-phenyl or NH₂; heteroalkyl is a 3-7-membered,saturated or up to triunsaturated heterocyclic ring which may compriseup to 4 heteroatoms which correspond to N, O or S, where theheterocyclic ring may be substituted up to three times by F, Cl, Br, CN,oxo, (C₁-C₄)-alkyl, —COOR13, (C₁-C₄)-alkylene-COOR13, COOR13,CON(R14)(R15), OR13, N(R14)(R15) or phenyl, where phenyl may besubstituted by COOR13; R7 is H, (C₁-C₆)-alkyl, where alkyl may besubstituted by OR13 or N(R14)(R15), or is O—(C₁-C₆)-alkyl,CO—(C₁-C₆)-alkyl or (C₀-C₆)-alkylene-COOR13; R8 is N(R18)(R19); R18, R19are, independently of one another, H, (C₁-C₁₀)-alkyl, (C₂-C₁₀)-alkenyl,(C₂-C₁₀)-alkynyl, (C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₆)-alkyl,(C₆-C₁₀)-aryl, (C₆-C₁₀)-aryl-(C₁-C₄)-alkyl,(C₆-C₁₀)-aryl-(C₂-C₄)-alkenyl, (C₆-C₁₀)-aryl-(C₂-C₄)-alkynyl,heteroaryl, heteroaryl-(C₁-C₄)-alkyl, heteroaryl-(C₂-C₄)-alkenyl,heteroaryl-(C₂-C₄)-alkynyl, where alkyl, alkenyl, alkynyl and cycloalkylmay be substituted more than once by F, Cl, CN, OR13, R13, CF₃, OCF₃,(C₆-C₁₀)-aryl, NH—C(═NR14)-N(R14)(R15), N(R14)(R15),C(═NR14)-N(R14)(R15), COOR13 or CON(R14)(R15), and where aryl may besubstituted more than once by F, Cl, CN, O—(C₁-C₆)-alkyl,O—(C₂-C₆)-alkenyl, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, CO—(C₁-C₆)-alkyl,CO—(C₂-C₆)-alkenyl, where alkyl and alkenyl may be substituted more thanonce by F, Cl, CH₃, OCH₃ or CN, NH—C(═NR14)-N(R14)(R15), N(R14)(R15),C(═NR14)-N(R14)(R15), COOR13, CON(R14)(R15), O-phenyl, phenyl orpyridyl; COOR13, CON—(R14)(R15), CO-heteroalkyl, CO—(C₆-C₁₀)-aryl orSO₂—(C₆-C₁₀)-aryl, where aryl may be substituted up to twice by F, Cl,CN, OH, (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl, CF₃, OCF₃, COOR13 orCON(R14)(R15); or the radicals R18 and R19 form with the nitrogen atomto which they are bonded a 3-7-membered, saturated heterocyclic ringwhich may comprise up to 2 further heteroatoms from the group of N, O orS, where the heterocyclic ring may be substituted up to three times byF, Cl, Br, OH, oxo, N(R16)(R17) or (C₁-C₄)-alkyl; or pharmaceuticallyacceptable salts thereof, provided the radicals R3, R4, R5, R6, R7, X,Y, and R8 do not have the following meanings at the same time: R3, R4 orR5 is CF₃; R6 is H or CF₃; R7 is H; X is O; and Y is O, S; R8 issubstituted or unsubstituted NH-phenyl wherein either the nitrogen atomor the phenyl ring is substituted or unsubstituted.
 2. A compound of theformula I as claimed in claim 1, wherein said compound has the structureof compound Ia:

wherein R9 is F, Cl, Br, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl,O—(C₂-C₆)-alkenyl, O—(C₂-C₆)-alkynyl, O—SO₂—(C₁-C₄)-alkyl, O—SO₂-phenyl,where the phenyl ring may be substituted up to twice by F, Cl, Br, CN,OR13, R13, CF₃, OCF₃, COOR13 or CON(R14)(R15), or S—(C₁-C₆)-alkyl,S—(C₂-C₆)-alkenyl, S—(C₂-C₆)-alkynyl, SO—(C₁-C₆)-alkyl,SO₂—(C₁-C₆)-alkyl, SO₂—NH₂, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,(C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl,—COOR13, (C₁-C₆)-alkylene-COOR13, CON(R14)(R15), —N(R14)(R15),(C₁-C₆)-alkylene-N(R14)(R15), NH—COR13, NH—CO-phenyl, NH—SO₂-phenyl orphenyl, where the phenyl ring may be substituted up to twice by F, Cl,Br, CN, OR13, R13, CF₃, OCF₃, COOR13 or CON(R14)(R15); R10, R11, R12independently of one another are H, F, Cl, Br, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-C₆)-alkyl, O—(C₂-C₆)-alkenyl, O—(C₂-C₆)-alkynyl,O—SO₂—(C₁-C₄)-alkyl, O—SO₂-phenyl, where the phenyl ring may besubstituted up to twice by F, Cl, Br, CN, OR13, R13, CF₃, OCF₃, COOR13or CON(R14)(R15), S—(C₁-C₆)-alkyl, S—(C₂-C₆)-alkenyl, S—(C₂-C₆)-alkynyl,SO—(C₁-C₆)-alkyl, SO₂—(C₁-C₆)-alkyl, SO₂—NH₂, (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl, —COOR13, (C₁-C₆)-alkylene-COOR13, COOR13, CON(R14)(R15), —N(R14)(R15), (C₁-C₆)-alkylene-N(R14)(R15),C₁-C₆)-alkylene-N(R14)(R15), N(R14)(R15), NH—COR13, NH—CO-phenyl,NH—SO₂-phenyl or phenyl, where the phenyl ring may be substituted up totwice by F, Cl, Br, CN, OR13, R13, CF₃, OCF₃, COOR13 or CON(R14)(R15);R13 is H, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl,(C₃-C₇)-cycloalkyl or (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl; R3, R4, R5,areindependently of one another H, F, Cl, Br, OH, CF₃, NO₂, CN, OCF₃,(C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, O—(C₁-C₁₀)-alkyl,O—(C₂-C₁₀)-alkenyl, O—(C₂-C₁₀)-alkynyl, S—(C₁-C₆)-alkyl,S—(C₂-C₆)-alkenyl, S—(C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl, where alkyl, alkenyl, alkynyl andcycloalkyl may be substituted more than once by F, Cl, Br, SO-phenyl,SO₂-phenyl, where the phenyl ring may be substituted by F, Cl, Br orR13, or OR13, COOR13, CON(R14)(R15), N(R14)(R15) or CO-heteroalkyl,O—SO—(C₁-C₆)-alkyl, O—SO₂—(C₁-C₆)-alkyl, O—SO₂—(C₆-C₁)-aryl,O—(C₆-C₁₀)-aryl, where aryl may be substituted up to twice by F, Cl, CN,OR13, R13, CF₃ or OCF₃, SO—(C₁-C₆)-alkyl, SO₂—(C₁-C₆)-alkyl,SO₂—(C₆-C₁₀)-aryl, where the phenyl ring may be substituted up to twiceby F, Cl, Br, CN, OR13, R13, CF₃, OCF₃, COOR13 or CON(R14)(R15),SO₂—N(R14)(R15), COOR13, CO-heteroalkyl, N(R14)(R15) or heteroalkyl; R6is F, Cl, Br, OH, CF₃, NO₂, CN, OCF₃, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,(C₂-C₆)-alkynyl, O—(C₁-C₁₀)-alkyl, O—(C₂-C₁₀)-alkenyl,O—(C₂-C₁₀)-alkynyl, S—(C₁-C₆)-alkyl, S—(C₂-C₆)-alkenyl,S—(C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl,where alkyl, alkenyl, alkynyl and cycloalkyl may be substituted morethan once by F, Cl, Br, SO-phenyl, SO₂-phenyl, where the phenyl ring maybe substituted by F, Cl, Br or R13, or OR13, COOR13, CON(R14)(R15),N(R14)(R15) or CO-heteroalkyl, or O—SO—(C₁-C₆)-alkyl,O—SO₂-(C₁-C₆)-alkyl, O—SO₂-(C₆-C₁₀)-aryl, O—(C₆-C₁₀)-aryl, where arylmay be substituted up to twice by F, Cl, CN, OR13, R13, CF₃ or OCF₃, orSO—(C₁-C₆)-alkyl, SO₂—(C₁-C₆)-alkyl, SO₂—(C₆-C₁₀)-aryl, where the phenylring may be substituted up to twice by F, Cl, Br, CN, OR13, R13, CF₃,OCF₃, COOR13 or CON(R14)(R15), or SO₂—N(R14)(R15), COOR13,CO-heteroalkyl, N(R14)(R15) or heteroalkyl; R14, R15 independently ofone another are H, (C₁-C₆)-alkyl, where alkyl may be substituted byN(R13)₂, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)alkyl, CO—(C₁-C₆)-alkyl, COO—(C₁-C₆)-alkyl,COO—(C₁-C₆)-alkylene-OCO—(C₁-C₆)-alkyl, CO-phenyl, COO-phenyl,COO—(C₁-C₆)-alkenyl-phenyl, OH, O—(C₁-C₆)-alkyl,O—(C₁-C₆)-alkenyl-phenyl or NH₂; or the radicals R14 and R15 form withthe nitrogen atom to which they are bonded a 3-7-membered, saturatedheterocyclic ring which may comprise up to 2 further heteroatoms fromthe group of N, O or S, where the heterocyclic ring may be substitutedup to three times by F, Cl, Br, OH, oxo, N(R16)(R17) or (C₁-C₄)-alkyl;R16, R17 independently of one another are H, (C₁-C₆)-alkyl, where alkylmay be substituted by N(R13)₂, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl,(C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl, CO—(C₁-C₆)-alkyl,COO—(C₁-C₆)-alkyl, COO—(C₁-C₆)-alkylene-OCO—(C₁-C₆)-alkyl, CO-phenyl,COO-phenyl, COO—(C₁-C₆)-alkenyl-phenyl, OH, O—(C₁-C₆)-alkyl,O—(C₁-C₆)-alkenyl-phenyl or NH₂; heteroalkyl is a 3-7-membered,saturated or up to triunsaturated heterocyclic ring which may compriseup to 4 heteroatoms selected from N, O or S, where the heterocyclic ringmay be substituted up to three times by F, Cl, Br, CN, oxo,(C₁-C₄)-alkyl, COOR13, (C₁-C₄)-alkylene-COOR13, CON(R14)(R15), OR13 orN(R14)(R15) or phenyl, where phenyl may be substituted by COOR13; R8 isN(R18)(R19); R18, R19 independently of one another are H,(C₁-C₁₀)-alkyl, (C₂-C₁₀)-alkenyl, (C₂-C₁₀)-alkynyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₆)-alkyl, (C₆-C₁₀)-aryl,(C₆-C₁₀)-aryl-(C₁-C₄)-alkyl, (C₆-C₁₀)-aryl-(C₂-C₄)-alkenyl,(C₆-C₁₀)-aryl-(C₂-C₄)-alkynyl, heteroaryl, heteroaryl-(C₁-C₄)-alkyl,heteroaryl-(C₂-C₄)-alkenyl, heteroaryl-(C₂-C₄)-alkynyl, where alkyl,alkenyl, alkynyl and cycloalkyl may be substituted more than once by F,Cl, CN, OR13, R13, CF₃, OCF₃, (C₆-C₁₀)-aryl, NH—C(═NR14)-N(R14)(R15),N(R14)(R15), C(═NR14)-N(R14)(R15), COOR13 or CON(R14)(R15), and wherearyl may be substituted more than once by F, Cl, CN, O—(C₁-C₆)-alkyl,O—(C₂-C₆)-alkenyl, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, CO—(C₁-C₆)-alkyl,CO—(C₂-C₆)-alkenyl, where alkyl and alkenyl may be substituted more thanonce by F, Cl, CH₃, OCH₃ or CN, or NH—C(═NR14)-N(R14)(R15), N(R14)(R15),C(═NR14)-N(R14)(R15), COOR13, CON(R14)(R15), O-phenyl, phenyl orpyridyl; COOR13, CON—(R14)(R15), CO-heteroalkyl, CO—(C₆-C₁₀)-aryl orSO₂—(C₆-C₁₀)-aryl, where aryl may be substituted up to twice by F, Cl,CN, OH, (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl, CF₃, OCF₃, COOR13 orCON(R14)(R15); or the radicals R18 and R19 form together with thenitrogen atom to which they are bonded a 3-7-membered, saturatedheterocyclic ring which may comprise up to 3 heteroatoms selected fromthe group of N, O or S, where the heterocyclic ring may be substitutedup to three times by F, Cl, Br, OH, oxo, N(R16)(R17) or (C₁-C₄)-alkyl;or a pharmaceutically acceptable salt thereof, provided the radical R8is not substituted or unsubstituted NH-phenyl wherein either thenitrogen atom or phenyl ring is substituted or unsubstituted.
 3. Acompound of the formula 1a as claimed in claim 2, wherein R9, R10, R11independently of one another are F or Cl; R12 is H; R13 is H,(C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl or(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl; R14, R15 are independently of oneanother H, (C₁-C₆)-alkyl, where alkyl may be substituted by N(R13)₂;heteroalkyl is a 3-7-membered, saturated or up to triunsaturatedheterocyclic ring which may comprise up to 4 heteroatoms selected fromN, O or S, where the heterocyclic ring may be substituted up to threetimes by F, Cl, Br, CN, oxo, (C₁-C₄)-alkyl, COOR13,(C₁-C₄)-alkylene-COOR13, CON(R14)(R15), OR13 or N(R14)(R15) or phenyl,where phenyl may be substituted by COOR13; R8 is N(R18)(R19); R18, R19are independently of one another H, (C₁-C₁₀)-alkyl, (C₂-C₁₀)-alkenyl,(C₂-C₁₀)-alkynyl, (C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₆)-alkyl,(C₆-C₁₀)-aryl, (C₆-C₁₀)-aryl-(C₁-C₄)-alkyl,(C₆-C₁₀)-aryl-(C₂-C₄)-alkenyl, (C₆-C₁₀)-aryl-(C₂-C₄)-alkynyl,heteroaryl, heteroaryl-(C₁-C₄)-alkyl, heteroaryl-(C₂-C₄)-alkenyl,heteroaryl-(C₂-C₄)-alkynyl, where alkyl, alkenyl, alkynyl and cycloalkylmay be substituted more than once by F, Cl, CN, OR13, R13, CF₃, OCF₃,(C₆-C₁₀)-aryl, NH—C(═NR14)-N(R14)(R15), N(R14)(R15),C(═NR14)—N(R14)(R15), COOR13 or CON(R14)(R15), and where aryl may besubstituted more than once by F, Cl, CN, O—(C₁-C₆)-alkyl,O—(C₂-C₆)-alkenyl, (C₁-C₆)-alkyl, (C₂-C₆yalkenyl, CO—(C₁-C₆)-alkyl,CO—(C₂-C₆)-alkenyl, where alkyl and alkenyl may be substituted more thanonce by F, Cl, CH₃, OCH₃ or CN, or NH—C(═NR14)-N(R14)(R15), N(R14)(R15),C(═NR14)-N(R14)(R15), COOR13, CON(R14)(R15), O-phenyl, phenyl orpyridyl; COOR13, CON—(R14)(R15), CO-heteroalkyl, CO—(C₆-C₁₀)-aryl orSO₂—(C₆-C₁₀)-aryl, where aryl may be substituted up to twice by F, Cl,CN, OH, (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl, CF₃, OCF₃, COOR13 orCON(R14)(R15); or the radicals R18 and R19 form together with thenitrogen atom to which they are bonded a 3-7-membered, saturatedheterocyclic ring which may comprise up to 3 heteroatoms selected fromthe group of N, O or S, where the heterocyclic ring may be substitutedup to three times by F, Cl, Br, OH, oxo, N(R16)(R17) or (C₁-C₄)-alkyl.4. A pharmaceutical composition comprising one or more of the compoundsas claimed in claim 1 and an acceptable carrier.
 5. A pharmaceuticalcomposition comprising one or more of the compounds as claimed in claim1, and an acceptable carrier, and at least one other active ingredient.6. A pharmaceutical composition as claimed in claim 5, wherein the otheractive ingredient comprises one or more antidiabetics, hypoglycemicactive ingredients, HMG-CoA reductase inhibitors, cholesterol absorptioninhibitors, PPAR gamma agonists, PPAR alpha agonists, PPAR alpha/gammaagonists, fibrates, MTP inhibitors, bile acid absorption inhibitors,CETP inhibitors, polymeric bile acid adsorbents, LDL receptor inducers,ACAT inhibitors, antioxidants, lipoprotein lipase inhibitors,ATP-citrate lyase inhibitors, squalene synthetase inhibitors,lipoprotein(a) antagonists, lipase inhibitors, insulins, sulfonylureas,biguanides, meglitinides, thiazolidinediones, α-glucosidase inhibitors,active ingredients which act on the ATP-dependent potassium channel ofthe beta cells, CART agonists, NPY agonists, MC4 agonists, orexinagonists, H3 agonists, TNF agonists, CRF agonists, CRF BP antagonists,urocortin agonists, β3 agonists, MSH (melanocyte-stimulating hormone)agonists, CCK agonists, serotonin reuptake inhibitors, mixedserotoninergic and noradrenergic compounds, 5HT agonists, bombesinagonists, galanin antagonists, growth hormones, growth hormone-releasingcompounds, TRH agonists, decoupling protein 2 or 3 modulators, leptinagonists, DA agonists (bromocriptine, Doprexin), lipase/amylaseinhibitors, PPAR modulators, RXR modulators or TR-β agonists oramphetamines.
 7. A process for producing a pharmaceutical compositioncomprising mixing one or more of the compounds as claimed in claim 1with an active ingredient and a pharmaceutically suitable carrier andconverting this mixture into a form suitable for administration.
 8. Amethod for reducing blood glucose, comprising administering to a subjectin need thereof, one or more compounds claimed in claim
 1. 9. A methodfor treating type 2 diabetes, comprising administering to a subject inneed thereof, one or more compounds claimed in claim
 1. 10. A method fortreating insulin resistance, comprising administering to a subject inneed thereof, one or more compounds claimed in claim 1.